Estrogen receptors α, β and GPER in the CNS and trigeminal system - molecular and functional aspects

Abstract

Background Migraine occurs 2–3 times more often in females than in males and is in many females associated with the onset of menstruation. The steroid hormone, 17β-estradiol (estrogen, E2), exerts its effects by binding and activating several estrogen receptors (ERs). Calcitonin gene-related peptide (CGRP) has a strong position in migraine pathophysiology, and interaction with CGRP has resulted in several successful drugs for acute and prophylactic treatment of migraine, effective in all age groups and in both sexes. Methods Immunohistochemistry was used for detection and localization of proteins, release of CGRP and PACAP investigated by ELISA and myography/perfusion arteriography was performed on rat and human arterial segments. Results ERα was found throughout the whole brain, and in several migraine related structures. ERβ was mainly found in the hippocampus and the cerebellum. In trigeminal ganglion (TG), ERα was found in the nuclei of neurons; these neurons expressed CGRP or the CGRP receptor in the cytoplasm. G-protein ER (GPER) was observed in the cell membrane and cytoplasm in most TG neurons. We compared TG from males and females, and females expressed more ER receptors. For neuropeptide release, the only observable difference was a baseline CGRP release being higher in the pro-estrous state as compared to estrous state. In the middle cerebral artery (MCA), we observed similar dilatory ER-responses between males and females, except for vasodilatory ERβ which we observed only in female arteries. Conclusion These data reveal significant differences in ER receptor expression between male and female rats. This contrasts to CGRP and PACAP release where we did not observe discernable difference between the sexes. Together, this points to a hypothesis where estrogen could have a modulatory role on the trigeminal neuron function in general rather than on the acute CGRP release mechanisms and vasomotor responses.

Estrogen exacerbates the nociceptive effects of peripheral serotonin on rat trigeminal sensory neurons

“…We are currently focused on identifying which nuclear and/or membrane estrogen receptors (ERα, ERβ, or GPER) are involved in potentiating the effects of 5HT on trigeminal sensory neurons. Previous studies have reported that ERα, ERβ, and GPER are present in trigeminal sensory neurons ( Chen et al, 2021 , Warfvinge et al, 2020 ).…”

Identifying New Antimigraine Targets: Lessons from Molecular Biology

“…As the ion channels are downstream of both the CGRP receptor and G i -coupled receptors, they might prove more efficient in blocking the hypersensitivity and pain. In addition, to fully understand the nonresponders, we need to understand factors such as migraine chronification [15] and hormonal influence on migraine pathology [91,92].…”

G protein‐coupled estrogen receptor in the rostral ventromedial medulla contributes to the chronification of postoperative pain

“… 16 Some studies have shown that estrogen and its nuclear receptors (ERα and ERβ) play a critical role in pain regulation. 17 , 18 , 19 , 20 However, few reports have directly investigated estrogenic effects on the descending pain modulation system, especially the function of GPER in the RVM on the chronification of postoperative pain.…”